Project Summary/Abstract Bacterial keratitis is one of the leading causes of corneal blindness. The primary medical therapy involves an intensive regimen of hourly antibiotic drops to eradicate the infection. A major unmet need for the treatment of bacterial keratitis is a sustained method of topical drug delivery to improve treatment efficacy and patient adherence. This proposal seeks to develop and test an antibiotic-eluting therapeutic contact lens (TCL) for the treatment of bacterial keratitis. The proposed research will test the hypothesis that because of continuous administration at therapeutic doses, an antibiotic-eluting TCL can safely and more effectively treat bacterial keratitis than the current standard of care, topical antibiotic drops. Moreover, we also hypothesize that TCLs can locally delivery high enough antibiotic concentrations so that it can overcome resistance and be used to treat ?fluoroquinolone-resistant? bacterial keratitis. Our approach uses a TCL design that incorporates a thin drug-polymer film within the periphery of a standard contact lens; this enables the release of large amounts of drug over days to weeks, while allowing unimpeded vision through the lens, and used materials that are all FDA-approved for use on the eye. Our preliminary studies that support this approach have demonstrated that a steroid-eluting contact lens can provide continuous drug levels to the cornea that exceeds that of hourly drops. We have formulated fluoroquinolone-eluting contact lenses that demonstrated controlled drug release for 2 days. The Specific Aims for this project are designed to systematically evaluate our hypotheses and evaluate the potential of this approach. In Aim 1 we confirm in vitro antibacterial effectiveness, perform cytotoxicity studies, and evaluate drug flux and biocompatibility in normal rabbit eyes.To ensure that the antibiotic-eluting TCL maintains the physical properties required for safe wear, we will characterize light transmittance, O2 transmissibility, water content, hydrophobicity, and elasticity of the TCL. In Aim 2 we will compare the efficacy of TCLs with hourly commercially available fluoroquinolone eye drops for the treatment of keratitis resulting from fluoroquinolone-susceptible Gram-negative (Pseudomonas aeruginosa) and Gram-positive (Staphylococcus aureus) bacteria, which are two of the most common causes of bacterial keratitis. In Aim 3, we will test the hypothesis that TCLs can provide enough antibiotic to overcome resistance and we will compare the treatment of TCL with vancomycin drops for the treatment of fluoroquinolone-resistant Staphylococcus aureus keratitis and with tobramycin drops for the treatment of fluoroquinolone-resistant Pseudomonas aeruginosa.